This invention relates to the treatment of pain and, primarily, this invention relates to drug compositions of nonracemic mixtures of d- and l-methadone and to the treatment of pain and particularly pain of mixed origin using the composition. In another aspect, this invention relates to the treatment of pain using a combination of d-methadone, l-methadone, or a non-racemic mixture of d- and l-methadone and an opioid antagonist such as naloxone, naltrexone, and the like.
Methadone is a well known opioid agonist that is widely used in alleviating chronic pain as well as in treatment of opioid addiction. Methadone, as typically used, is a racemic mixture of the l- and d-isomers. It is well-established that the l-isomer of methadone has mu-opioid activity as well as N-methyl-D-aspartate (NMDA) receptor antagonist activity. It also possesses ability to block re-uptake of noradrenaline and serotonin. Unlike the l-isomer, the d-isomer of methadone has practically no mu-opioid activity, but has NMDA receptor antagonist activity and ability to reverse tolerance to opioid agonists. This is discussed at length in U.S. Pat. No. 6,008,258 to Inturrisi which is incorporated herein by reference in its entirety. U.S. Pat. No. 6,008,258 is primarily concerned with the use of the d-isomer of methadone for the treatment of pain.
U.S. Pat. No. 6,008,258 briefly describes different types of pain, i.e., neuropathic pain, somatic pain, and visceral pain, but makes no distinction in the treatment of these different types of pain. This patent describes treating any type of pain with d-methadone. It is not concerned with the use of l-methadone or with d,l-methadone, the latter of which has already been extensively mentioned in the literature.
The d-isomer of methadone has a longer half-life than the racemic mixture and in doses high enough to provide an effect in animal studies can cause temporary motor paralysis. Administering d-methadone with opioids is difficult because of the significantly longer half-life. It is even worse for intrathecal delivery because it disappears from CSF significantly faster than morphine or hydromorphone. Development of tolerance to d-methadone alone, but not to the non-opioid activity of l-methadone or d,l-methadone has been shown by J. D. Leander & P. E. McCleary, “Opioid and Nonopioid Behavioral Effects of Methadone Isomers,” J. Pharmacol. Exp. Ther., 220:592-596, 1982, which is incorporated herein by reference in its entirety.